BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

Objective This study aimed to analyze the characteristics and clinical significance of peripheral lymphocytic subsets and cytokine levels, including interleukin 1β(IL-1β), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, tumor necrosis factor α(TNF-α), interferon γ(IFN-γ) and IFN-α, in patients with primary biliary cholangitis (PBC), to provide some novel insights into the pathogenesis of PBC. Methods We retrospectively collected clinical features and laboratory data from hospitalized patients who were primarily diagnosed with PBC and from healthy physical examinees at the Third People's Hospital of Changzhou between January 1, 2023, and June 30, 2024. Results A total of 152 PBC patients and 96 healthy controls who met the inclusion and exclusion criteria were enrolled. Significant differences were observed in baseline characteristics and laboratory data between the two groups. After the propensity score matching (PSM) analysis, 61 PBC patients and 61 healthy controls were successfully matched, ensuring that the general characteristics (age and gender) of the two groups were balanced and comparable. Compared to the control group, the proportion of peripheral lymphocytes was significantly higher in the PBC group (31.9% vs. 17.8%), primarily due to an increase in CD4⁺ T cells (46.77% vs. 41.19%), while CD8⁺T cells were significantly decreased (19.73% vs. 22.07%). Notably, the proportions of CD4⁺ programmed cell death 1 (PD-1)⁺ T and CD8⁺PD-1⁺ T cells were elevated, with CD8⁺PD-1⁺ T cells showing a significant positive correlation with the severity of liver inflammation (r=0.41). Furthermore, the mitochondrial mass (MM) of CD4⁺ T cells was significantly increased in PBC patients, whereas no significant changes were observed in the MM of CD8⁺ T cells or the mitochondrial membrane potential (MMP) of CD3⁺ T cells. Additionally, the plasma levels of cytokines, such as IL-4, IL-8, IL-10 and IFN-α, were abnormally elevated. The plasma levels of IL-5 and IL-1β were negatively correlated with the stage of liver fibrosis in patients with PBC (r=-0.52). Conclusion The overactivation and proliferation of CD4⁺ T cells, along with the suppression of CD8⁺ T cell function and increased PD-1 expression leads to T cell exhaustion, indicating significant immunological alterations in PBC patients. These changes are closely associated with the disease progression. Additionally, cytokines are likely involved in the immune regulation process of PBC and may influence the pathogenic mechanisms of the disease. Regular monitoring of lymphocyte subsets and cytokine levels can help assess the immune status and disease activity in patients with PBC, thereby guiding the individualized treatment strategies.
Humans ; Male ; Female ; Middle Aged ; Liver Cirrhosis, Biliary/blood* ; Retrospective Studies ; T-Lymphocyte Subsets/immunology* ; Aged ; Cytokines/blood* ; Adult ; CD8-Positive T-Lymphocytes/immunology*

Objective To investigate the effect of the glutathione peroxidase 4(GPx4)on mouse so-matic cell reprogramming.Methods To compare the expressions of GPx4 in OG2 mouse embryonic fibroblast(OG2-MEF)cells(MEFs group)and mouse embryonic stem cells(mESC,mESCs group),the expression lev-el of intracellular GPx4 was determined by transcriptome sequencing technique and Western blot.To verify the effect of GPx4 on the efficiency of the somatic cells reprogramming,the complete open reading frame se-quence of GPx4 gene and its selenocysteine insertion sequence(SECIS)were connected to the retroviral vector pMXs for constructing the overexpressed plasmid pMXs-GPx4.Gpx4-targeting short hairpin RNA(shRNA)was synthesized and connected to pSUPER vector,GPx4 shRNA1 and GPx4 shRNA2 were constructed to knockdown GPx4 expression.The above plasmids were co-transfected with pMXs-Sox2,pMXs-Klf4 and pMXs-Oct4 into MEF cells for reprogramming induction to obtain the pMXs no-load control group(pMXs NC),pMXs GPx4 group,pSUPER no-load control group(pSUPER NC),GPx4 shRNA1 group and GPx4 shRNA2 group.The expressions of GPx4 gene and multifunctional marker genes Rex1,Sox2,Dappa3,Sall4,Oct4 and Nanog were detected by real-time fluorescence quantitative PCR.The induced pluripotent stem cells(iPSC)were detected by immunofluorescence staining;the number of iPSC clones generation was detected by alkaline phosphatase staining of pluripotent stem cells;the GPx4 protein expression was detected by Western blot.Results The mRNA and protein expression of GPx4 in the mESCs group was higher than that in the MEFs group;compared with the pMXs NC group,the expression level of GPx4 mRNA in the pMXs GPx4 group was significantly increased;compared with the pSUPER NC group,the GPx4 mRNA and protein levels in the GPx4 shRNA1 group and GPx4 shRNA2 group were decreased(P＜0.05);the iPSC clone number in the pMXs GPx4 group was higher than that in the pMXs NC group,but the difference was not statistically significant(P＞0.05).The number of iPSC clones in the GPx4 shRNA1 group and GPx4 shRNA2 group was significantly lower than that in the pSUPER NC group,and the difference was statistically significant(P＜0.05).After completing the reprogramming,compared with the original MEF cells,the expression levels of various pluripotent marker genes Rex1,Sox2,Dappa3,Sall4,Oct4 and Nanog in the generated iPSC of each group were increased.Conclusion GPx4 knockdown could inhibit the efficiency of somatic cell reprogram-ming,its generated induced pluripotent stem cells have the normal pluripotent gene expression ability.

In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis-a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.
Humans ; Mice ; Animals ; Non-alcoholic Fatty Liver Disease/metabolism* ; NF-kappa B/metabolism* ; Organelle Biogenesis ; Retrospective Studies ; Mice, Inbred C57BL ; Obesity/metabolism* ; Liver ; Inflammation/metabolism* ; Body Weight ; Lipid Metabolism ; Lipids ; Diet, High-Fat/adverse effects*

Objective    To evaluate the survival results of surgical resection (SR) and CT-guided percutaneous ablation (PA) for stageⅠnon-small cell lung cancer (NSCLC). Methods    The PubMed, Web of Science, EMbase, The Cochrane Library, CNKI, VIP, Wanfang databases from inception to June 2021 were searched to collect comparative studies on the survival results between SR and CT-guided PA treatment for stageⅠNSCLC. RevMan 5.3 software was used for statistical analysis of data. Results    A total of 3 114 patients were included in 11 studies. The results of meta-analysis showed that compared with the PA group, the SR group had a higher 2-year postoperative overall survival (OS) rate (OR=1.44, 95%CI 1.00-2.06, P=0.05), 3-year postoperative OS rate (OR=2.37, 95%CI 1.47-3.81, P<0.001), 5-year OS rate (OR=1.64, 95%CI 1.19-2.28, P<0.01), 5-year progression-free survival rate after operation (OR=2.43, 95%CI 1.54-3.82, P<0.001) and lower local recurrence rate (OR=0.26, 95%CI 0.13-0.54, P<0.001). There were no statistical differences between the two groups in terms of 1-year postoperative OS rate, 1-year, 2-year, and 3-year tumor-related survival rates, 1-year, 2-year tumor-free survival rates, or distant postoperative recurrence rate (P>0.05). Conclusion    For patients with stageⅠNSCLC with optimal basic conditions, surgery is a more appropriate treatment. For patients who cannot withstand surgical injuries or refuse surgery, CT-guided PA is also a potential alternative treatment. However, this conclusion needs  to be verified by prospective controlled trials with larger sample sizes and a more rigorous design.

Objective:To screen the potential biomarkers for the diagnosis and differential diagnosis of immune-mediated demyelinating diseases by tandem mass tags (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology.Methods:Twenty patients with demyelinating diseases (demyelinating group) and 10 patients with noninflammatory neurological diseases (NND group) from Beijing Tiantan Hospital affiliated to Capital Medical University from January 2020 to January 2021 were enrolled in this study. The demyelinating group included 10 patients with Guillain-Barre syndrome (GBS subgroup) and 10 patients with multiple sclerosis (MS subgroup). TMT proteomics was used to screen out the different protein expression patterns between the demyelinating group and the NND group and between the GBS subgroup and the MS subgroup (difference>2 or<0.5 and with statistical significance), and String database was used to perform gene ontology (GO) analysis and Kyoto encyclopedia of gene and genomes (KEGG) analysis on the pathways involved in the differently expressed proteins between the groups. In addition, 80 demyelinating patients (demyelinating diseases validation group) and 40 healthy subjects (healthy control group) were selected for retrospective analysis of general lipid indexes. The demyelinating diseases validation group included 40 GBS patients (GBS validation group) and 40 MS patients (MS validation group). Receiver operating characteristic (ROC) curve was obtained to evaluate the value of general lipid indexes for the diagnosis of demyelinating diseases and the differential diagnosis between GBS and MS groups.Results:A total of 362 proteins were detected by TMT proteomics. There were 101 differentially expressed proteins between the demyelinating group and the NND group, and 45 differentially expressed proteins between the GBS group and the MS group. Compared with the NND group, GO enrichment analysis showed that the top five enrichment pathways in the demyelinating group were macrophage colony stimulating factor and receptor complex, negative regulation of cholesterol input, negative regulation of very low density lipoprotein particle clearance, triglyceride-rich lipoprotein particle remodeling, and cholesterol reverse transport. Compared with MS group, the top five enriched pathways in GBS group were high-density lipoprotein particle receptor binding, negative regulation of very low density lipoprotein particle remodeling, negative regulation of cholesterol input, negative regulation of very low density lipoprotein particle clearance, and medium density lipoprotein particle. KEGG enrichment analysis results showed that differentially expressed proteins in the demyelinating group and the NND group were enriched in 8 pathways, including phosphatidylinositide 3-kinases-protein kinase B signaling pathway, complement and coagulation cascade reaction, extracellular matrix and its receptor interaction, Staphylococcus aureus infection, cholesterol metabolism, RAS signaling pathway, phagosome, and mitogen-activated protein kinase signaling pathway. Differentially expressed proteins in GBS group and MS group were enriched in 9 pathways: cholesterol metabolism, complement and coagulation cascade, platelet activation, peroxisome proliferators-activated receptors signaling pathway, vitamin digestion and absorption, novel coronavirus infection, fat digestion and absorption, axon guidance, and neutrophil extracellular trap formation pathway. The levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) were significantly higher, while high density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (apoA1) levels were significantly lower in the demyelinating disease validation group than in the healthy control group (all P<0.05 or 0.01). Area under the curve (AUC) of TG, TC, HDL-C, LDL-C, apoA1 and apoB alone or in combination for the diagnosis of immune-mediated demyelinating diseases was 0.746, 0.643, 0.798, 0.703, 0.806, 0.708 and 0.868, respectively. The AUC of HDL-C, apoA1, LDL-C and apoB for differential diagnosis between GBS and MS was 0.692, 0.653, 0.632, 0.695 and 0.718, respectively. Conclusions:There are differences in cerebrospinal fluid proteomics between patients with immune-mediated demyelinating disease and patients with NND, GBS and MS, and the differentially expressed protein patterns mainly exist in the pathways related to lipid metabolism. Lipid related indicators may be used as biomarkers for the diagnosis and differential diagnosis of immune-mediated demyelinating disease.

Objective:To summarize critical cases of emergency helicopter transferring between hospitals and improve the quality and safety of critical care.Methods:The task records of Guangxi Aviation Medical Rescue Training Base from September 2017 to September 2020 were retrieved. The mission acceptance, implementation results, disease spectrum composition, pre-transfer preparation and medical intervention on board were summarized.Results:① General information: a total of 168 patients of helicopter transfer requests were registered, of which 36 patients were transferred, 35 patients were successful, 1 patient had cardiac arrest during the landing phase, and died several hours after continuous resuscitation. Of the 36 patients 30 were males and 6 were females, with median age of 50.5 (29.8, 66.0) years old, the average transfer time was (54.95±17.89) minutes, and the average transfer distance was (205.74±74.68) km. ② Disease spectrum included 11 cases of stroke (30.55%), 7 cases of trauma (19.45%), 5 cases of severe pneumonia (13.89%), 5 cases of heart and macro-vascular diseases (13.89%), 5 cases of abdominal emergency (13.89%), and 3 other conditions (8.33%).③ Severity: 31 patients (86.11%) were severe (≥15) according to acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score; 19 patients (52.78%) were high-risk emergency transport (≥6) according to Hamilton early warning score (HEWS); 6 patients (85.71% of trauma patients) were severe trauma (≥16) according to injury severity score (ISS). ④ Preparation before transfer: remote consultation was carried out to evaluate the latest state of the patient's condition, especially the respiratory and circulatory conditions. Relevant items were reviewed and emergency treatments were implemented when necessary. Targeted preparation was made for accidents that might occur during transfer, such as electrocardiogram (94.44%), blood gas analysis (94.44%), brain CT (36.11%) and other auxiliary examinations, endotracheal intubation or tracheotomy (72.22%), deep vein catheterization (91.67%), placement of gastric tube (86.11%) and urinary tube (88.89%), adjustment of sedative (38.89%), vasoactive drugs (58.33%) and drugs for dehydration and lowering intracranial pressure (33.33%), and fixation of fracture (11.11%), etc. ⑤ On-board medical intervention: cardiac monitoring, blood pressure, respiration and blood oxygen monitoring were carried out in all patients. The parameters of patients using ventilator were adjusted in time (66.67%). The dosage of patients using micropump was adjusted in time (91.67%). Other aspects included the use of sedative and analgesics (38.89%), sputum suction nursing (75.00%), all kinds of catheter nursing (endotracheal intubation/incision nursing of 72.22%, indwelling catheter nursing of 88.89%), and cardiopulmonary resuscitation for patient with cardiac arrest (2.78%).Conclusion:As the patients transferred by helicopter are mainly those of critically ill at this stage, the requirements for airborne medical equipment and rescue technology are high, and there is an urgent need to establish technical specifications and personnel training standards.

Objective:To investigate the prognostic factors of renal function after nephron sparing surgery (NSS) in renal tumor patients.Methods:The data of 115 patients who underwent NSS in our hospital from December 2016 to December 2018 were retrospectively analyzed. There were 75 males and 40 females, aged (49.50±12.94) years. The body mass index was (24.59±3.59) kg/m 2. The maximum diameter of the tumor was (3.66±1.32) cm. The R. E.N.A.L. score was (6.43±1.60). Laparoscopic partial nephrectomy was performed in 61 cases and robot-assisted laparoscopic partial nephrectomy was performed in 54 cases, and all of which were successfully completed. Operative time, WIT and postoperative pathological results were recorded. Blood creatinine value, GFR of affected kidney, GFR of healthy kidney, total GFR, GFR preserving rate (the ratio of postoperative GFR to preoperative GFR), functioning parenchymal volume (FPV) of the affected kidneys, and FPV preserving rate of the affected kidneys (the ratio of postoperative FPV and preoperative FPV) were recorded 6 months after surgery. FPV was measured by the ellipsoid approximation on CT images before and after surgery. Paired sample t test was used to compare GFR and FPV before and after surgery. Spearman rank correlation analysis was used to evaluate the correlation between the study factors and GFR preserving rate of the affected kidneys. Multivariate linear regression models were used to analyze independent predictors of renal function of the affected kidneys. Independent sample t test was used for comparison between group of WIT≤25 min and group of WIT>25 min. Results:All of the 115 patients in this study underwent successfully operations, with the median operation time of 135(75-245) min, and WIT(24.57±5.51) min. Postoperative GFR of the affected kidneys(35.50±7.81)ml/(min·1.73 m 2) was significantly different from preoperative GFR( P<0.001). The FPV preserving rate of the affected kidneys was (84.28±4.37)%, which was significantly lower than that preoperative FPV of the affected kidneys ( P<0.001). Spearman rank correlation analysis showed that there was a strong positive correlation between the FPV preserving rate of the affected kidneys and the GFR preserving rate of the affected kidneys ( r=0.802), WIT was negatively correlated with the GFR preserving rate of the affected kidneys ( r=-0.503). Multiple linear regression analysis showed that preoperative GFR of the affected kidneys ( b=-0.150, P=0.008), WIT ( b=-0.443, P<0.001) and the FPV preserving rate of the affected kidneys ( b=1.638, P<0.001) were independent predictors of the GFR preserving rate of the affected kidneys. WIT>25 min group had a significantly lower GFR preserving rate of the affected kidneys than WIT≤25 min group [(68.77±10.88)% vs.(79.34±8.88)%, P<0.001]. Conclusions:In the case of short WIT (<30 min), the reservation of normal renal tissue is the most important variable prognostic factor of renal function after NSS, and short WIT plays a secondary role. Under the premise of complete tumor resection, normal renal tissue should be reserved as much as possible and WIT should be controlled within 25 min.

Objective:To explore the clinical significance of recurrent laryngeal nerve inlet zone(RLNIZ) lymph node metastasis in papillary thyroid cancer(PTC).Methods:The clinical data of the clinicopathologic characteristics of 738 cases with papillary thyroid cancer at our centers from Jul 2017 to Jun 2018 was retrospectively reviewed. 108 cases with RLNIZ lymph node dissection for pathological examination were included. The relationship between metastasis of RLNIZ lymph node and clinicopathologic characteristics was analyzed.Results:RLNIZ lymph node was detected in 12.3%(91/738)cases, the mean lymph node number in RLNIZ was 1.5±0.7, and 30.8%(28/91) cases suffered RLNIZ lymph node metastasis. RLNIZ lymph node metastasis(LNM) is associated with tumor size( P=0.028), capsular invasion( P=0.019), No. of central compartment LNM( P<0.001) and lateral neck LNM( P<0.001). No. of central compartment LNM was found to be the independent risk factor of RLNIZ lymph node metastasis. The incidence of dysphagia and inferior parathyroid damage was 0.9%(1/108)respectively. Conclusions:RLNIZ lymph node metastasis is common among PTC patients , therefore, RLNIZ lymph node should be routinely removed especially in patients with tumor size over 1cm、suspected capsular invasion and lateral neck lymph node metastasis confirmed by preoperative imaging examination.

[Abstract] Objective: To construct a circRNA profile of esophageal squamous cell carcinoma (ESCC) and analyze differentially expressed circRNAs. Methods: Samples were taken from 3 patients with esophageal squamous cell carcinoma who were hospitalized in the Department of Thoracic Surgery, Jintan Hospital, Jiangsu University from June 2018 to February 2019. The circRNA expression profile was constructed by high-throughput sequencing technique, and the circRNA differentially expressed in 3 pairs of esophageal squamous cell carcinoma tissues and adjacent tissues was detected. The biological functions and related signal pathways of these circRNA were analyzed by GO and KEGG techniques. Results: By comparing the expression levels of circRNA between esophageal squamous cell carcinoma and adjacent tissues, 905 differentially expressed circRNA were found, of which 404 were up-regulated and 501 were down-regulated. hsa_circ_0004390 was the CIRC RNA with the highest up-regulation factor (FC=7.9712), and novel_circ_0012687 was the one with the highest down-regulation factor. GO and KEGG analysis showed that these circRNA may be involved in biological processes such as cell cycle, cell components and protein binding of cancer cells, and signal pathways such as Hippo and cGMP-PKG. Conclusion: The expression profile analysis of circRNA in esophageal squamous cell carcinoma showed that the significantly differentially expressed circRNA could be used as a potential biomarker of esophageal squamous cell carcinoma.